Project Summary Investigating the broader efficacy of sEH inhibition and specifically our IND candidate, EC5026, has indicated that it is efficacious against chemotherapy induced peripheral neuropathy (CIPN). This painful neuropathy develops from chemotherapy treatment, is notoriously difficult to treat, and can lead to discontinuation of life-prolonging cancer treatments. Thus, new therapeutic approaches are urgently needed. We propose here to test the efficacy of our soluble epoxide hydrolase inhibitor, EC5026, and a potential backup, EC5029, for their efficacy in CIPN and to characterize this activity with three classes of chemotherapeutics in models of CIPN. We will also investigate if EC5026 has potential drug-drug interaction with approved chemotherapeutics or alters immune cells function. We will assess the effects of sEHI on the lipid metabolome and probe for changes in endoplasmic reticulum stress and axonal outgrowth in neurons. The PK/ADME properties of EC5026 have been determined and a pilot 28-day safety study in dogs has been completed with good results. We propose here to more fully characterize the analgesic potential of our compound and investigate on and off target actions in CIPN models and model systems relevant to cancer therapy.